Anantha K. Murthy

Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer.

PURPOSE To compare two published schedules of cisplatin plus fluorouracil (5-FU) infusion and radiation as either sequential or concomitant treatment for toxicity and efficacy in patients with unresectable head and neck cancer. PATIENTS AND METHODS This was a randomized trial between cisplatin 100 mg/m2 over 15 minutes on day 1 plus 5-FU 1.0 g/m2 by continuous infusion on days 1 to 5, repeated every 3 weeks for three cycles, followed by 70 Gy of radiation in 7 to 8 weeks, versus cisplatin 60 mg/m2 over 15 minutes on day 1 plus 5-FU 800 mg/m2 by continuous infusion on days 1 to 5 plus radiation 2 Gy on days 1 to 5, repeated every other week for seven cycles. Unresectable head and neck squamous cancer patients not previously treated with radiation or chemotherapy and with a performance status of 0 to 2 were stratified by tumor (T) and node (N) groupings and performance status and randomized. RESULTS Two hundred fifteen patients were entered and 214 analyzed, 107 on each arm. After all treatment, overall response rates were different (P = .003), with similar complete response rates, but more partial responses and fewer patients with no change or progression with concomitant treatment. Cox regression analysis for progression-free survival identified concomitant treatment (P = .003), Radiation Therapy Oncology Group (RTOG) stage III grouping (P < .0001), performance status (P = .0002), concomitant treatment (P = .003), and treating institution (P = .006) as significant. The sequential and concomitant treatments showed similar distant failure patterns (10% and 7%, respectively), but divergent regional failure rates (55% and 39%). Severe and worse toxic events were similar between the treatment programs, but radiation-induced mucositis combined with cisplatin-induced water-losing nephropathy, in the concomitant arm only, demanded more supportive care. Survival duration was similar between the treatment arms, but significantly more patients in the sequential arm died of their cancer (P = .011). CONCLUSION Concomitant treatment offered improved disease control, predominantly of regional disease, but benefit was dependent on the experience of the treating institution. Translation of this benefit into improved survival is not yet evident, with an excess of deaths from other causes in the concomitant arm.

A randomized trial of adjuvant chemotherapy in head and neck cancer.

Ninety-five patients with squamous cell carcinoma of the head and neck were entered into a randomized study testing a two-week course of induction chemotherapy with methotrexate and leucovorin given prior to regional therapy. In addition, following regional therapy, patients randomized to chemotherapy were to receive similar methotrexate courses every three months for one year. Poor tolerance to this regimen after radiation and surgery led to a change in the chemotherapy following regional therapy to a combination of Adriamycin (Adria Laboratories, Columbus, Ohio) and cisplatin every three weeks for four cycles after the first 35 patients had been entered. Nine cases were ineligible and four lacked any follow-up data, leaving 82 analyzable cases. Using Cox regression analysis, no differences in the percentage of patients achieving disease control, the relapse-free survival, or the overall survival were identified between any treatment group. As has been described in many pilot studies of induction chemotherapy of head and neck cancer, chemotherapy responders had a more favorable disease-free survival than chemotherapy nonresponders in the total group of patients receiving adjuvant chemotherapy. However, correcting for imbalances in the expected three year disease-free survival of these patients, based on their disease site and stage, erased this difference, indicating tumor response to this regimen of chemotherapy is not an independent factor affecting disease outcome. The division of patients into arbitrary prognostic categories based on the expected outcome for each specific tumor site and stage proved to be a useful method for balancing treatment groups, given the multiple site-stage combinations within the upper aerodigestive tract. The defined prognostic categories were the single most sensitive predictors of relapse-free and overall survival.

Combined simultaneous cisplatin/fluorouracil chemotherapy and split course radiation in head and neck cancer.

Fifty-three patients with stage III (eight patients, 15%), stage IV (36 patients, 68%), or recurrent disease (nine patients, 17%) entered a study of simultaneous cisplatin, 60 mg/m2 day 1, fluorouracil (5-FU) infusion, 800 mg/m2 days 1 to 5, and radiation, 2 Gy days 1 to 5, every other week for a total of seven cycles (70 Gy in 13 weeks). Patient acceptance was high, with only two patients (4%) refusing to complete therapy. The median actual dose delivered was 88% of the planned dose for cisplatin, 78% for 5-FU, and 70 Gy for radiation. Weight loss of 10% or more and severe mucositis were the most common side effects (53% and 48% incidence, respectively). All patients were followed at least 1 year (median, 51 months). While the complete response rate (55%) seemed no better than that reported in other series, freedom of progression of regional disease (73%), and the survival of all patients (median, 37 months) were substantially improved. Only 33% of partial responders have failed regionally, while 15% of complete responders have failed regionally (P greater than .10), which indicates that clinical assessment of response was unreliable. Stage, the presence of N3 disease, and delivery of less than the median actual dose received of 5-FU (but not cisplatin) were significantly associated with failure. This regimen is feasible and tolerable in this difficult patient population. It generally requires no special forced feeding techniques. Survival results from this limited institution study appear better than those using sequential multimodality therapies. With such favorable regional control, this approach may offer an alternative in the future to radical surgery and radiation in resectable disease. More definitive evaluation seems warranted.

Treatment of advanced head and neck cancer with concomitant radiation and chemotherapy

Forty-four patients with predominantly inoperable or recurrent head and neck cancers were treated with combined chemotherapy (CT) and radiation therapy (RT) in a Phase I/II study. CT and RT were combined in a concomitant fashion to take advantage of radiosensitizing properties of the chemotherapeutic agents. Each treatment cycle consisted of cisplatin 60 mg/M2 on day 1, 5-FU infusion at a dose of 800 mg/M2 per day continuously for 5 days and RT at 200 cGy per day, days 1 through 5. The treatment cycle was repeated every 2 weeks for 7 cycles in patients treated curatively and for 2 to 6 cycles in patients treated palliatively due to prior radiation therapy or the presence of metastatic disease. Regional control was achieved in 98% of the patients. Regional control has persisted in 87% of the patients treated curatively with a minimum follow-up of 24 months. Distant failure occurred in 23% of this group. Actuarial survival of 2 years for the curative group is 66%. Concomitant combination of radiation with radiation potentiating chemotherapeutic agents shows promise of increase in local control.

Should multicentric disease be an absolute contraindication to the use of breast-conserving therapy?

PURPOSE Multicentric cancer is present in a large proportion of mastectomies performed as treatment of breast cancer; it has been considered a contraindication to breast conservation. METHODS AND MATERIALS We reviewed the records of our patients with Stage I or II breast cancer treated with breast conserving surgery and radiation therapy over a 13-year period. Twenty-seven patients had two or more nodules of grossly visible cancer separated by histologically normal breast tissue. All patients had grossly negative margins of excision; however, four patients had microscopically positive margins. Nine patients had positive axillary nodes. All patients received radiation therapy to the breast postoperatively, with a median dose of 50.4 Gy in 28 fractions; 11 patients also received a boost dose of 6-20 Gy to the tumor bed. Eleven patients were given adjuvant chemotherapy and one patient was given adjuvant tamoxifen. RESULTS With a median follow-up of 53 months, only one patient has relapsed in the breast (3.7%); that patient relapsed in multiple distant sites at the same time. Three patients have died of disseminated disease; the actuarial survival and disease-free survival rates at 4 years are 89%. CONCLUSION Breast conservation may be considered for patients with multicentric breast cancer discovered at the time of histologic examination. For patients with multicentric disease detected prior to surgery, breast conserving therapy may be appropriate as long as: (1) all clinically and radiographically apparent abnormalities are removed, (2) clear margins of resection are achieved, and (3) there is no extensive intraductal component.

Concomitant cisplatin/5-FU infusion and radiotherapy in advanced head and neck cancer: 8-year analysis of results

The purpose of this study was to analyze long‐term follow‐up of a single institutions experience with a regimen of concomitant cisplatin/fluorouracil (5‐FU) infusion and radiation given every other week. This analysis was stimulated by results of a randomized trial showing superiority for this regimen over induction cisplatin/5‐FU chemotherapy followed by radiotherapy, especially in regional disease control.

Cytotoxicity and influence on radiation dose response curve of cis-diamminedichloroplatinum II (cis-DDP)

Abstract Exponentially growing Chinese hamster ovary (CHO) cells were exposed to varying doses of Cis-diamminedichloroplatinum II ( cis DDP) for I hour. Cytotoxicity was found to be dose dependent and the dose response curve has shoulder and exponential portions. D o on the exponential portion of the curve was found to be 2.8 μ/ml. The values of D q and the extrapolation number (n) corrected for single cells were found to be 3.1 μ/ml and 12.0 respectively. The influence of exposure to cis DDP on the radiation dose response curve was also studied. The radiation dose response curve of the CHO cells not exposed to cis DDP is characterized by a D o of 139 rad. The values of D q and n corrected for single cells are 105 rad and 4.5 respectively. Exposure to 8 /ml of cis DDP for 1 hour decreased D o to 102 rad when exposure was immediately prior to irradiation and to 106 rad when the exposure was immediately after irradiation. D q and n were found to be 140 rad and 18 for pre-radiation exposure and 137 rad and 15 for post-radiation exposure. This influence on the radiation dose response curve was not found to be cis DDP dose dependent since at higher concentration of cis DDP (10 μ/ml, 12 μ/ml, 16 μ/ml) D o , D p and n were found to be the same as at 8 μ/ml.

Is contralateral neck treatment necessary in early carcinoma of the tonsil

Abstract One of the most distressing complications of radiation therapy of the head and neck cancers is xerostomia. Treatment of both parotid glands to high doses would be expected to result in high probability of symptomatic xerostomia. Treatment of early carcinomas of the tonsil with techniques to include bilateral upper neck nodes would result in xerostomia whereas treatment limited to the primary and ipsilateral neck only would avoid it. The latter technique has been used in 32 patients with carcinoma of the tonsil treated in Rush-Presbyterian-St. Lukes Medical Center from 1965 through 1975. Of 20 patients with No or N1 disease treated this way, there were no contralateral neck recurrences with controlled primary and ipsilateral neck.

Concomitant chemotherapy and split-course radiation for cure and preservation of speech and swallowing in head and neck cancer

To assess the ability of simultaneous cisplatin, 5‐Fluorouracil, and radiation to substitute for surgery and radiation in advanced head and neck cancer, we have retrospectively selected from our phase II study a subgroup of 29 patients having primary disease requiring either more than a hemiglossec‐tomy or a laryngectomy for control. Patients included 22 with stage IV and 7 with stage III disease, 12 tongue, 10 hypopharynx, and 7 larynx primaries. The treatment consisted of concurrent cisplatin, 5‐Fluo‐rouracil, and split‐course radiation every other week for a total of 7 cycles within 13 weeks. With a median follow‐up of 5 years, 86% of patients had preservation of speech and/or swallowing function. Median survival was 45 months, with 14 (48%) patients currently alive and disease free, 11 (38%) dead from their cancer, and 4 (14%) dead of other causes. The overall failure rate was 38%. Advanced‐stage presence of N3 nodal disease and fewer than 7 cycles of chemotherapy received were significantly associated with increasing failure rates. This program of concomitant cisplatin, 5‐Fluorouracil, and radiation produced control rates quite competitive with surgery and radiation and is appropriate for definitive testing in a randomized trial.

Technique for breast irradiation using custom blocks conforming to the chest wall contour

A technique for the treatment of the breast and regional nodes is presented. The technique involves the use of tangential fields to treat the breast and chest wall. Customized blocks which conform to the slope of the chest wall are made for each tangent field. Simulation and treatment with this technique requires no special equipment. The setup is simple and quick. A three-field technique is also described using the custom half-beam blocks; this technique avoids the use of tangential field corner blocks, thus simplifying simulation and treatment.